Antigenic and genetic characterization of the novel influenza A H1N1 virus indicated that the virus contained a unique combination of gene segments from North American and Eurasian lineages of swine influenza viruses. The viruses isolated from human cases of the 2009 pandemic H1N1 (pH1N1) virus infection were antigenically homogeneous and antigenically similar to North American swine H1N1 viruses, but distinct from seasonal human influenza A H1N1 viruses. The hypothesis of original antigenic sin (OAS) states that the imprint established by an individuals first influenza infection governs the antibody response thereafter. Subsequent influenza virus infections result in an antibody response against the original infecting virus, impairing the immune response against a newer influenza virus. We sought evidence of OAS in humans that had prior H1N1 infections with viruses of variable antigenic distance from the 2009 pH1N1 virus, including viruses from 1935 through 1999. Analysis of paired samples of human sera taken before and after vaccination with a monovalent inactivated 2009 pH1N1 vaccine showed a significantly greater fold-rise in antibody titer against the 2009 pH1N1 virus compared to H1N1 viruses that circulated during the childhood of each subject. Thus, prior experience with H1N1 viruses did not result in an impairment of the antibody response against the 2009 pH1N1 vaccine. Our data suggest that prior exposure to H1N1 viruses did not impair the immune response against the 2009 pH1N1 virus. A live attenuated influenza virus (LAIV) vaccine is licensed for healthy adults 2-49 years of age. This vaccine is administered by nasal spray. Neutralizing antibody in the serum has been found to be a correlate of protection for TIV, but the immune correlates of protection for LAIV are not known. Defining the origin and nature of transcriptional responses to LAIV in upper respiratory tract will be a highly informative first step in a systems approach toward understanding the molecular basis of viral replication restriction and the regulation of the local mucosal immune responses following LAIV administration. In FY13, in collaboration with colleagues at Stanford University, we undertook a natural history study using a systems biology approach to identify LAIV replication niches among a variety of URT cell types and characterize the host immune response to LAIV. Data analysis is in progress.